Site staff perspectives on communicating trial results to participants: Cost and feasibility results from the Show RESPECT cluster randomised, factorial, mixed-methods trial.

BACKGROUND/AIMS: Sharing trial results with participants is an ethical imperative but often does not happen. Show RESPECT (ISRCTN96189403) tested ways of sharing results with participants in an ovarian cancer trial (ISRCTN10356387). Sharing results via a printed summary improved patient satisfaction. Little is known about staff experience and the costs of communicating results with participants. We report the costs of communication approaches used in Show RESPECT and the views of site staff on these approaches. METHODS: We allocated 43 hospitals (sites) to share results with trial participants through one of eight intervention combinations (2 × 2 × 2 factorial; enhanced versus basic webpage, printed summary versus no printed summary, email list invitation versus no invitation). Questionnaires elicited data from staff involved in sharing results. Open- and closed-ended questions covered resources used to share results and site staff perspectives on the approaches used. Semi-structured interviews were conducted. Interview and free-text data were analysed thematically. The mean additional site costs per participant from each intervention were estimated jointly as main effects by linear regression. RESULTS: We received questionnaires from 68 staff from 41 sites and interviewed 11 site staff. Sites allocated to the printed summary had mean total site costs of sharing results £13.71/patient higher (95% confidence interval (CI): -3.19, 30.60; p = 0.108) than sites allocated no printed summary. Sites allocated to the enhanced webpage had mean total site costs £1.91/patient higher (95% CI: -14, 18.74; p = 0.819) than sites allocated to the basic webpage. Sites allocated to the email list had costs £2.87/patient lower (95% CI: -19.70, 13.95; p = 0.731) than sites allocated to no email list. Most of these costs were staff time for mailing information and handling patients' queries. Most site staff reported no concerns about how they had shared results (88%) and no challenges (76%). Most (83%) found it easy to answer queries from patients about the results and thought the way they were allocated to share results with participants would be an acceptable standard approach (76%), with 79% saying they would follow the same approach for future trials. There were no significant effects of the randomised interventions on these outcomes. Site staff emphasised the importance of preparing patients to receive the results, including giving opt-in/opt-out options, and the need to offer further support, particularly if the results could confuse or distress some patients. CONCLUSIONS: Adding a printed summary to a webpage (which significantly improved participant satisfaction) may increase costs to sites by ~£14/patient, which is modest in relation to the cost of trials. The Show RESPECT communication interventions were feasible to implement. This information could help future trials ensure they have sufficient resources to share results with participants.

Contraceptive use and pregnancy planning in Britain during the first year of the COVID-19 pandemic: findings from a large, quasi-representative survey (Natsal-COVID).

BACKGROUND: Contraceptive services were significantly disrupted during the COVID-19 pandemic in Britain. We investigated contraception-related health inequalities in the first year of the pandemic. METHODS: Natsal-COVID Wave 2 surveyed 6658 adults aged 18-59 years between March and April 2021, using quotas and weighting to achieve quasi-representativeness. Our analysis included sexually active participants aged 18-44 years, described as female at birth. We analysed contraception use, contraceptive switching due to the pandemic, contraceptive service access, and pregnancy plannedness. RESULTS: Of 1488 participants, 1619 were at risk of unplanned pregnancy, of whom 54.1% (51.0%-57.1%) reported routinely using effective contraception in the past year. Among all participants, 14.3% (12.5%-16.3%) reported switching or stopping contraception due to the pandemic. 3.2% (2.0%-5.1%) of those using effective methods pre-pandemic switched to less effective methods, while 3.8% (2.5%-5.9%) stopped. 29.3% (26.9%-31.8%) of at-risk participants reported seeking contraceptive services, of whom 16.4% (13.0%-20.4%) reported difficulty accessing services. Clinic closures and cancelled appointments were commonly reported pandemic-related reasons for difficulty accessing services. This unmet need was associated with younger age, diverse sexual identities and anxiety symptoms. Of 199 pregnancies, 6.6% (3.9%-11.1%) scored as 'unplanned'; less planning was associated with younger age, lower social grade and unemployment. CONCLUSIONS: Just under a third of participants sought contraceptive services during the pandemic and most were successful, indicating resilience and adaptability of service delivery. However, one in six reported an unmet need due to the pandemic. COVID-induced inequalities in service access potentially exacerbated existing reproductive health inequalities. These should be addressed in the post-pandemic period and beyond.

Initial Impacts of COVID-19 on Sex Life and Relationship Quality in Steady Relationships in Britain: Findings from a Large, Quasi-representative Survey (Natsal-COVID).

Intimate relationships are ubiquitous and exert a strong influence on health. Widespread disruption to them may impact wellbeing at a population level. We investigated the extent to which the first COVID-19 lockdown (March 2020) affected steady relationships in Britain. In total, 6,654 participants aged 18-59 years completed a web-panel survey (July-August 2020). Quasi-representativeness was achieved via quota sampling and weighting. We explored changes in sex life and relationship quality among participants in steady relationships (n = 4,271) by age, gender, and cohabitation status, and examined factors associated with deterioration to a lower-quality relationship. A total of 64.2% of participants were in a steady relationship (of whom 88.9% were cohabiting). A total of 22.1% perceived no change in their sex-life quality, and 59.5% no change in their relationship quality. Among those perceiving change, sex-life quality was more commonly reported to decrease and relationship quality to improve. There was significant variation by age; less often by gender or cohabitation. Overall, 10.6% reported sexual difficulties that started/worsened during lockdown. In total, 6.9% reported deterioration to a "lower quality" relationship, more commonly those: aged 18-24 and aged 35-44; not living with partner (women only); and reporting depression/anxiety and decrease in sex-life quality. In conclusion, intimate relationship quality is yet another way in which COVID-19 has led to divergence in experience.

Estimands in cluster-randomized trials: choosing analyses that answer the right question.

BACKGROUND: Cluster-randomized trials (CRTs) involve randomizing groups of individuals (e.g. hospitals, schools or villages) to different interventions. Various approaches exist for analysing CRTs but there has been little discussion around the treatment effects (estimands) targeted by each. METHODS: We describe the different estimands that can be addressed through CRTs and demonstrate how choices between different analytic approaches can impact the interpretation of results by fundamentally changing the question being asked, or, equivalently, the target estimand. RESULTS: CRTs can address either the participant-average treatment effect (the average treatment effect across participants) or the cluster-average treatment effect (the average treatment effect across clusters). These two estimands can differ when participant outcomes or the treatment effect depends on the cluster size (referred to as 'informative cluster size'), which can occur for reasons such as differences in staffing levels or types of participants between small and large clusters. Furthermore, common estimators, such as mixed-effects models or generalized estimating equations with an exchangeable working correlation structure, can produce biased estimates for both the participant-average and cluster-average treatment effects when cluster size is informative. We describe alternative estimators (independence estimating equations and cluster-level analyses) that are unbiased for CRTs even when informative cluster size is present. CONCLUSION: We conclude that careful specification of the estimand at the outset can ensure that the study question being addressed is clear and relevant, and, in turn, that the selected estimator provides an unbiased estimate of the desired quantity.

How did the COVID-19 pandemic affect access to condoms, chlamydia and HIV testing, and cervical cancer screening at a population level in Britain? (Natsal-COVID).

OBJECTIVES: To investigate how differential access to key interventions to reduce STIs, HIV and their sequelae changed during the COVID-19 pandemic. METHODS: British participants (18-59 years) completed a cross-sectional web survey 1 year (March-April 2021) after the initial lockdown in Britain. Quota-based sampling and weighting resulted in a quasi-representative population sample. We compared Natsal-COVID data with Natsal-3, a household-based probability sample cross-sectional survey (16-74 years) conducted in 2010-2012. Reported unmet need for condoms because of the pandemic and uptake of chlamydia testing/HIV testing/cervical cancer screening were analysed among sexually experienced participants (18-44 years) (n=3869, Natsal-COVID; n=8551, Natsal-3). ORs adjusted for age and other potential confounders describe associations with demographic and behavioural factors. RESULTS: In 2021, 6.9% of women and 16.2% of men reported unmet need for condoms because of the pandemic. This was more likely among participants: aged 18-24 years, of black or black British ethnicity, and reporting same-sex sex (past 5 years) or one or more new relationships (past year). Chlamydia and HIV testing were more commonly reported by younger participants, those reporting condomless sex with new sexual partners and men reporting same-sex partners; a very similar distribution to 10 years previously (Natsal-3). However, there were differences during the pandemic, including stronger associations with chlamydia testing for men reporting same-sex partners; with HIV testing for women reporting new sexual partners and with cervical screening among smokers. CONCLUSIONS: Our study suggests differential access to key primary and secondary STI/HIV prevention interventions continued during the first year of the COVID-19 pandemic. However, there was not strong evidence that differential access has changed during the pandemic when compared with 2010-2012. While the pandemic might not have exacerbated inequalities in access to primary and secondary prevention, it is clear that large inequalities persisted, typically among those at greatest STI/HIV risk.

Recruitment and implementation challenges were common in stepped-wedge cluster randomized trials: Results from a methodological review.

OBJECTIVE: To explore challenges in recruitment and intervention implementation in recent stepped-wedge cluster randomized trials (SW-CRTs). STUDY DESIGN AND SETTING: We searched PubMed to identify primary reports of SW-CRTs (2019-2020). Two reviewers independently screened studies and extracted data from each report. A recruitment challenge was defined as a planned number of clusters or participants not achieved or any reported changes made to the design to address recruitment difficulties. An implementation challenge was defined as early, late, or no implementation of the intervention in at least one cluster. RESULTS: Of 55 SW-CRTs, 18 (33%) had a recruitment challenge, 23 (42%) had none, and for 14 (26%) it was impossible to judge. At least one implementation challenge was present in 24 (44%), eight (15%) had none, and for 23 (42%) it was impossible to judge. Of the 35 (64%) trials with recruitment or implementation challenges, 18 (72%) had one or more modifications of their design, most often a modification of the trial duration. CONCLUSION: Investigators must be aware of the risks of recruitment or implementation challenges when considering the use of an SW-CRT design. Mitigating strategies should be adopted when planning the trial. More transparent reporting of planned and actual design features is required.

Initial impacts of the COVID-19 pandemic on sexual and reproductive health service use and unmet need in Britain: findings from a quasi-representative survey (Natsal-COVID).

BACKGROUND: The COVID-19 pandemic has affected sexual and reproductive health (SRH) service use and unmet need, but the impact is unknown. We aimed to determine the proportion of participants reporting sexual risk behaviours, SRH service use and unmet need, and to assess remote sexually transmitted infection (STI) testing service use after the first national lockdown in Britain. METHODS: We used data from the National Surveys of Sexual Attitudes and Lifestyles (Natsal)-COVID cross-sectional, quasi-representative web survey (Natsal-COVID Wave 1). Adults aged 18-59 years who resided in England, Scotland, or Wales completed the survey between July 29 and Aug 10, 2020, which included questions about the approximate 4-month period after announcement of the initial lockdown in Britain (March 23, 2020). Quota-based sampling and weighting were used to achieve a quasi-representative population sample. Participants aged 45-59 years were excluded from services analysis due to low rates of SRH service use. Among individuals aged 18-44 years, we estimated reported SRH service use and inability to access, and calculated age-adjusted odds ratios (aORs) among sexually experienced individuals (those reporting any sexual partner in their lifetime) and sexually active individuals (those reporting any sexual partner in the past year). Unweighted denominators and weighted estimates are presented hereafter. FINDINGS: 6654 individuals had complete interviews and were included in the analysis. Among 3758 participants aged 18-44 years, 82·0% reported being sexually experienced, and 73·7% reported being sexually active. 20·8% of sexually experienced participants aged 18-44 years reported using SRH services in the 4-month period. Overall, 9·7% of 3108 participants (9·5% of men; 9·9% of women) reported being unable to use a service they needed, although of the participants who reported trying but not being able to use a SRH service at least once, 76·4% of participants also reported an instance of successful use. 5·9% of 1221 sexually active men and 3·6% of 1560 sexually active women reported use of STI-related services and 14·8% of 1728 sexually experienced women reported use of contraceptive services, with SRH service use highest among individuals aged 18-24 years. Sexually active participants reporting condomless sex with new partners since lockdown were much more likely to report using STI-related services than those who did not report condomless sex (aOR 23·8 [95% CI 11·6-48·9]) for men, 10·5 [3·9-28·2] for women) and, among men, were also more likely to have an unsuccessful attempt at STI-service use (aOR 13·3 [5·3-32·9]). Among 106 individuals who reported using STI testing services, 64·4% accessed services remotely (telephone, video, or online). Among 2581 women aged 25-59 years, 2·4% reported cervical screening compared with an estimated 6% in a comparable 4-month period before the pandemic. INTERPRETATION: Many people accessed SRH care during the initial lockdown; however, young people and those reporting sexual risk behaviours reported difficulties in accessing services and thus such services might need to address a backlog of need. FUNDING: Wellcome Trust, The Economic and Social Research Council, The National Institute for Health Research, Medical Research Council/Chief Scientist Office and Public Health Sciences Unit, and UCL Coronavirus Response Fund.

Impacts of COVID-19 on sexual behaviour in Britain: findings from a large, quasi-representative survey (Natsal-COVID).

OBJECTIVES: Physical restrictions imposed to combat COVID-19 dramatically altered sexual lifestyles but the specific impacts on sexual behaviour are still emerging. We investigated physical and virtual sexual activities, sexual frequency and satisfaction in the 4 months following lockdown in Britain in March 2020 and compared with pre-lockdown. METHODS: Weighted analyses of web panel survey data collected July/August 2020 from a quota-based sample of 6654 people aged 18-59 years in Britain. Multivariable regression took account of participants' opportunity for partnered sex, gender and age, to examine their independent associations with perceived changes in sexual frequency and satisfaction. RESULTS: Most participants (86.7%) reported some form of sex following lockdown with physical activities more commonly reported than virtual activities (83.7% vs 52.6%). Altogether, 63.2% reported sex with someone ('partnered sex') since lockdown, three-quarters of whom were in steady cohabiting relationships. With decreasing relationship formality, partnered sex was less frequently reported, while masturbation, sex toy use and virtual activities were more frequently reported. Around half of all participants perceived no change in partnered sex frequency compared with the 3 months pre-lockdown, but this was only one-third among those not cohabiting, who were more likely to report increases in non-partnered activities than those cohabiting. Two-thirds of participants perceived no change in sexual satisfaction; declines were more common among those not cohabiting. Relationship informality and younger age were independently associated with perceiving change, often declines, in sexual frequency and satisfaction. CONCLUSIONS: Our quasi-representative study of the British population found a substantial minority reported significant shifts in sexual repertoires, frequency and satisfaction following the introduction of COVID-19 restrictions. However, these negative changes were perceived by some more than others; predominantly those not cohabiting and the young. As these groups are most likely to experience adverse sexual health, it is important to monitor behaviour as restrictions ease to understand the longer term consequences, including for health services.

Methodology of Natsal-COVID Wave 2: A large, quasi-representative, longitudinal survey measuring the impact of COVID-19 on sexual and reproductive health in Britain.

Background: The National Surveys of Sexual Attitudes and Lifestyles COVID study (Natsal-COVID) was designed to understand the impact of COVID-19 on Britain's sexual and reproductive health (SRH). Natsal-COVID Wave 1 survey and qualitative follow-up interviews were conducted in 2020. The Wave 2 survey was designed to capture one-year prevalence estimates for key SRH outcomes and measure changes over the first year of the pandemic. We describe the Wave 2 survey methodology and assess the sample representativeness. Methods: Natsal-COVID Wave 2 was conducted March-April 2021; approximately one year after the start of Britain's first national lockdown. Data were collected using an online web-panel survey administered by Ipsos. The sample comprised a longitudinal sample of Wave 1 participants who had agreed to re-contact plus a sample of participants residing in Britain, aged 18-59, including a boost sample comprising people aged 18-29. Questions covered reproductive health, relationships, sexual behaviour and SRH service use. Quotas and weighting were used to achieve a quasi-representative sample of the British population. Comparisons were made with recent national probability surveys, Natsal-3 (2010-12) and Natsal-COVID Wave 1 to understand bias. Results: A total of 6,658 individuals completed the survey. In terms of gender, age, ethnicity, and rurality, the weighted Natsal-COVID Wave 2 sample was like the general population. Participants were less likely to be married or to report being in good health than the general population. The longitudinal sample (n=2,098) were broadly like participants who only took part in Wave 1 but were older. Among the sexually active, longitudinal participants were less likely to report multiple sexual partners or a new sexual partner in the past year compared to those who only took part in Wave 1. Conclusions: Natsal-COVID collected longitudinal, quasi-representative population data to enable evaluation of the population-level impact of COVID-19 on SRH and to inform policy.

The Alpha variant was not associated with excess nosocomial SARS-CoV-2 infection in a multi-centre UK hospital study.

OBJECTIVES: Recently emerging SARS-CoV-2 variants have been associated with an increased rate of transmission within the community. We sought to determine whether this also resulted in increased transmission within hospitals. METHODS: We collected viral sequences and epidemiological data of patients with community and healthcare associated SARS-CoV-2 infections, sampled from 16th November 2020 to 10th January 2021, from nine hospitals participating in the COG-UK HOCI study. Outbreaks were identified using ward information, lineage and pairwise genetic differences between viral sequences. RESULTS: Mixed effects logistic regression analysis of 4184 sequences showed healthcare-acquired infections were no more likely to be identified as the Alpha variant than community acquired infections. Nosocomial outbreaks were investigated based on overlapping ward stay and SARS-CoV-2 genome sequence similarity. There was no significant difference in the number of patients involved in outbreaks caused by the Alpha variant compared to outbreaks caused by other lineages. CONCLUSIONS: We find no evidence to support it causing more nosocomial transmission than previous lineages. This suggests that the stringent infection prevention measures already in place in UK hospitals contained the spread of the Alpha variant as effectively as other less transmissible lineages, providing reassurance of their efficacy against emerging variants of concern.

Testing approaches to sharing trial results with participants: The Show RESPECT cluster randomised, factorial, mixed methods trial.

BACKGROUND: Sharing trial results with participants is an ethical imperative but often does not happen. We tested an Enhanced Webpage versus a Basic Webpage, Mailed Printed Summary versus no Mailed Printed Summary, and Email List Invitation versus no Email List Invitation to see which approach resulted in the highest patient satisfaction with how the results were communicated. METHODS AND FINDINGS: We carried out a cluster randomised, 2 by 2 by 2 factorial, nonblinded study within a trial, with semistructured qualitative interviews with some patients (ISRCTN96189403). Each cluster was a UK hospital participating in the ICON8 ovarian cancer trial. Interventions were shared with 384 ICON8 participants who were alive and considered well enough to be contacted, at 43 hospitals. Hospitals were allocated to share results with participants through one of the 8 intervention combinations based on random permutation within blocks of 8, stratified by number of participants. All interventions contained a written plain English summary of the results. The Enhanced Webpage also contained a short video. Both the Enhanced Webpage and Email contained links to further information and support. The Mailed Printed Summary was opt-out. Follow-up questionnaires were sent 1 month after patients had been offered the interventions. Patients' reported satisfaction was measured using a 5-point scale, analysed by ordinal logistic regression estimating main effects for all 3 interventions, with random effects for site, restricted to those who reported receiving the results and assuming no interaction. Data collection took place in 2018 to 2019. Questionnaires were sent to 275/384 randomly selected participants and returned by 180: 90/142 allocated Basic Webpage, 90/133 Enhanced Webpage; 91/141 no Mailed Printed Summary, 89/134 Mailed Printed Summary; 82/129 no Email List Invitation, 98/146 Email List Invitation. Only 3 patients opted out of receiving the Mailed Printed Summary; no patients signed up to the email list. Patients' satisfaction was greater at sites allocated the Mailed Printed Summary, where 65/81 (80%) were quite or very satisfied compared to sites with no Mailed Printed Summary 39/64 (61%), ordinal odds ratio (OR) = 3.15 (1.66 to 5.98, p < 0.001). We found no effect on patient satisfaction from the Enhanced Webpage, OR = 1.47 (0.78 to 2.76, p = 0.235) or Email List Invitation, OR = 1.38 (0.72 to 2.63, p = 0.327). Interviewees described the results as interesting, important, and disappointing (the ICON8 trial found no benefit). Finding out the results made some feel their trial participation had been more worthwhile. Regardless of allocated group, patients who received results generally reported that the information was easy to understand and find, were glad and did not regret finding out the results. The main limitation of our study is the 65% response rate. CONCLUSIONS: Nearly all respondents wanted to know the results and were glad to receive them. Adding an opt-out Mailed Printed Summary alongside a webpage yielded the highest reported satisfaction. This study provides evidence on how to share results with other similar trial populations. Further research is needed to look at different results scenarios and patient populations. TRIAL REGISTRATION: ISRCTN: ISRCTN96189403.

Optimal design of cluster randomized trials allowing unequal allocation of clusters and unequal cluster size between arms.

There are sometimes cost, scientific, or logistical reasons to allocate individuals unequally in an individually randomized trial. In cluster randomized trials we can allocate clusters unequally and/or allow different cluster size between trial arms. We consider parallel group designs with a continuous outcome, and optimal designs that require the smallest number of individuals to be measured given the number of clusters. Previous authors have derived the optimal allocation ratio for clusters under different variance and/or intracluster correlations (ICCs) between arms, allowing different but prespecified cluster sizes by arm. We derive closed-form expressions to identify the optimal proportions of clusters and of individuals measured for each arm, thereby defining optimal cluster sizes, when cluster size can be chosen freely. When ICCs differ between arms but the variance is equal, the optimal design allocates more than half the clusters to the arm with the higher ICC, but (typically only slightly) less than half the individuals and hence a smaller cluster size. We also describe optimal design under constraints on the number of clusters or cluster size in one or both arms. This methodology allows trialists to consider a range for the number of clusters in the trial and for each to identify the optimal design. Except if there is clear prior evidence for the ICC and variance by arm, a range of values will need to be considered. Researchers should choose a design with adequate power across the range, while also keeping enough clusters in each arm to permit the intended analysis method.

Optimal design of cluster randomised trials with continuous recruitment and prospective baseline period.

BACKGROUND: Cluster randomised trials, like individually randomised trials, may benefit from a baseline period of data collection. We consider trials in which clusters prospectively recruit or identify participants as a continuous process over a given calendar period, and ask whether and for how long investigators should collect baseline data as part of the trial, in order to maximise precision. METHODS: We show how to calculate and plot the variance of the treatment effect estimator for different lengths of baseline period in a range of scenarios, and offer general advice. RESULTS: In some circumstances it is optimal not to include a baseline, while in others there is an optimal duration for the baseline. All other things being equal, the circumstances where it is preferable not to include a baseline period are those with a smaller recruitment rate, smaller intracluster correlation, greater decay in the intracluster correlation over time, or wider transition period between recruitment under control and intervention conditions. CONCLUSION: The variance of the treatment effect estimator can be calculated numerically, and plotted against the duration of baseline to inform design. It would be of interest to extend these investigations to cluster randomised trial designs with more than two randomised sequences of control and intervention condition, including stepped wedge designs.

Methodology of Natsal-COVID Wave 1: a large, quasi-representative survey with qualitative follow-up measuring the impact of COVID-19 on sexual and reproductive health in Britain.

Background: Britain's National Surveys of Sexual Attitudes and Lifestyles (Natsal) have been undertaken decennially since 1990 and provide a key data source underpinning sexual and reproductive health (SRH) policy. The COVID-19 pandemic disrupted many aspects of sexual lifestyles, triggering an urgent need for population-level data on sexual behaviour, relationships, and service use at a time when gold-standard in-person, household-based surveys with probability sampling were not feasible. We designed the Natsal-COVID study to understand the impact of COVID-19 on the nation's SRH and assessed the sample representativeness. Methods: Natsal-COVID Wave 1 data collection was conducted four months (29/7-10/8/2020) after the announcement of Britain's first national lockdown (23/03/2020). This was an online web-panel survey administered by survey research company, Ipsos MORI. Eligible participants were resident in Britain, aged 18-59 years, and the sample included a boost of those aged 18-29. Questions covered participants' sexual behaviour, relationships, and SRH service use. Quotas and weighting were used to achieve a quasi-representative sample of the British general population. Participants meeting criteria of interest and agreeing to recontact were selected for qualitative follow-up interviews. Comparisons were made with contemporaneous national probability surveys and Natsal-3 (2010-12) to understand bias. Results: 6,654 participants completed the survey and 45 completed follow-up interviews. The weighted Natsal-COVID sample was similar to the general population in terms of gender, age, ethnicity, rurality, and, among sexually-active participants, numbers of sexual partners in the past year. However, the sample was more educated, contained more sexually-inexperienced people, and included more people in poorer health. Conclusions: Natsal-COVID Wave 1 rapidly collected quasi-representative population data to enable evaluation of the early population-level impact of COVID-19 and lockdown measures on SRH in Britain and inform policy. Although sampling was less representative than the decennial Natsals, Natsal-COVID will complement national surveillance data and Natsal-4 (planned for 2022).

Imiquimod versus podophyllotoxin, with and without human papillomavirus vaccine, for anogenital warts: the HIPvac factorial RCT.

BACKGROUND: The comparative efficacy, and cost-effectiveness, of imiquimod or podophyllotoxin cream, either alone or in combination with the quadrivalent HPV vaccine (Gardasil®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) in the treatment and prevention of recurrence of anogenital warts is not known. OBJECTIVE: The objective was to compare the efficacy of imiquimod and podophyllotoxin creams to treat anogenital warts and to assess whether or not the addition of quadrivalent human papillomavirus vaccine increases wart clearance or prevention of recurrence. DESIGN: A randomised, controlled, multicentre, partially blinded factorial trial. Participants were randomised equally to four groups, combining either topical treatment with quadrivalent human papillomavirus vaccine or placebo. Randomisation was stratified by gender, a history of previous warts and human immunodeficiency virus status. There was an accompanying economic evaluation, conducted from the provider perspective over the trial duration. SETTING: The setting was 22 sexual health clinics in England and Wales. PARTICIPANTS: Participants were patients with a first or repeat episode of anogenital warts who had not been treated in the previous 3 months and had not previously received quadrivalent human papillomavirus vaccine. INTERVENTIONS: Participants were randomised to 5% imiquimod cream (Aldara®; Meda Pharmaceuticals, Takeley, UK) for up to 16 weeks or 0.15% podophyllotoxin cream (Warticon®; GlaxoSmithKlein plc, Brentford, UK) for 4 weeks, which was extended to up to 16 weeks if warts persisted. Participants were simultaneously randomised to quadrivalent human papillomavirus vaccine (Gardasil) or saline control at 0, 8 and 24 weeks. Cryotherapy was permitted after week 4 at the discretion of the investigator. MAIN OUTCOME MEASURES: The main outcome measures were a combined primary outcome of wart clearance at week 16 and remaining wart free at week 48. Efficacy analysis was by logistic regression with multiple imputation for missing follow-up values; economic evaluation considered the costs per quality-adjusted life-year. RESULTS: A total of 503 participants were enrolled and attended at least one follow-up visit. The mean age was 31 years, 66% of participants were male (24% of males were men who have sex with men), 50% had a previous history of warts and 2% were living with human immunodeficiency virus. For the primary outcome, the adjusted odds ratio for imiquimod cream versus podophyllotoxin cream was 0.81 (95% confidence interval 0.54 to 1.23), and for quadrivalent human papillomavirus vaccine versus placebo, the adjusted odds ratio was 1.46 (95% confidence interval 0.97 to 2.20). For the components of the primary outcome, the adjusted odds ratio for wart free at week 16 for imiquimod versus podophyllotoxin was 0.77 (95% confidence interval 0.52 to 1.14) and for quadrivalent human papillomavirus vaccine versus placebo was 1.30 (95% confidence interval 0.89 to 1.91). The adjusted odds ratio for remaining wart free at 48 weeks (in those who were wart free at week 16) for imiquimod versus podophyllotoxin was 0.98 (95% confidence interval 0.54 to 1.78) and for quadrivalent human papillomavirus vaccine versus placebo was 1.39 (95% confidence interval 0.73 to 2.63). Podophyllotoxin plus quadrivalent human papillomavirus vaccine had inconclusive cost-effectiveness compared with podophyllotoxin alone. LIMITATIONS: Hepatitis A vaccine as control was replaced by a saline placebo in a non-identical syringe, administered by someone outside the research team, for logistical reasons. Sample size was reduced from 1000 to 500 because of slow recruitment and other delays. CONCLUSIONS: A benefit of the vaccine was not demonstrated in this trial. The odds of clearance at week 16 and remaining clear at week 48 were 46% higher with vaccine, and consistent effects were seen for both wart clearance and recurrence separately, but these differences were not statistically significant. Imiquimod and podophyllotoxin creams had similar efficacy for wart clearance, but with a wide confidence interval. The trial results do not support earlier evidence of a lower recurrence with use of imiquimod than with use of podophyllotoxin. Podophyllotoxin without quadrivalent human papillomavirus vaccine is the most cost-effective strategy at the current vaccine list price. A further larger trial is needed to definitively investigate the effect of the vaccine; studies of the immune response in vaccine recipients are needed to investigate the mechanism of action. TRIAL REGISTRATION: Current Controlled Trials. Current Controlled Trials ISRCTN32729817 and EudraCT 2013-002951-14. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 47. See the NIHR Journals Library website for further project information.

The HIPvac [Human papillomavirus infection: a randomised controlled trial of Imiquimod cream (5%) versus Podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts] trial compared two commonly used creams to treat genital warts: 0.15% podophyllotoxin cream (Warticon^®; GlaxoSmithKlein plc, Brentford, UK) and 5% imiquimod cream (Aldara^®; Meda Pharmaceuticals, Takeley, UK). It also investigated whether or not a vaccine used to prevent human papillomavirus infection, quadrivalent human papillomavirus vaccine (Gardasil^®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA), could help treat warts or prevent them from coming back in patients whose warts had been cleared. The HIPvac trial was a randomised controlled trial involving 503 patients with warts attending sexual health clinics in England and Wales. The creams and the vaccine were well tolerated; there was some soreness where the cream was applied, but no unexpected side effects. When deciding which treatment was better, we looked at whether or not the warts had cleared by 16 weeks after starting treatment and, if cleared, whether or not they returned by 48 weeks. We compared the creams against each other, and the addition of vaccine against no vaccine (a placebo injection). Patients were allowed to have cryotherapy (freezing treatment) as well, if the investigator advised this. We also calculated the value for money of each type of treatment. The two creams were very similar in how well they worked to clear the warts. One difference was that podophyllotoxin cream worked slightly quicker. The number of patients given cryotherapy was about the same for both types of cream. We had expected that recurrence of warts after treatment with imiquimod cream might be less than after treatment with podophyllotoxin cream, but, in fact, the two creams were similar. Quadrivalent human papillomavirus vaccine did not improve clearance of warts or reduce the chance of recurrence, but the result remains inconclusive. If we had been able to recuit 1000 participants as originally planned, we might have been able to be more certain about whether there was any benefit of vaccination. Further research would be needed to investigate any possible effect. The two creams offered similar value for money in treating warts. Giving patients the vaccine in addition to the cream is not good value for money at its current list price, given the uncertainty about the benefit it offers.

Cluster randomised trials with different numbers of measurements at baseline and endline: Sample size and optimal allocation.

BACKGROUND/AIMS: Published methods for sample size calculation for cluster randomised trials with baseline data are inflexible and primarily assume an equal amount of data collected at baseline and endline, that is, before and after the intervention has been implemented in some clusters. We extend these methods to any amount of baseline and endline data. We explain how to explore sample size for a trial if some baseline data from the trial clusters have already been collected as part of a separate study. Where such data aren't available, we show how to choose the proportion of data collection devoted to the baseline within the trial, when a particular cluster size or range of cluster sizes is proposed. METHODS: We provide a design effect given the cluster size and correlation parameters, assuming different participants are assessed at baseline and endline in the same clusters. We show how to produce plots to identify the impact of varying the amount of baseline data accounting for the inevitable uncertainty in the cluster autocorrelation. We illustrate the methodology using an example trial. RESULTS: Baseline data provide more power, or allow a greater reduction in trial size, with greater values of the cluster size, intracluster correlation and cluster autocorrelation. CONCLUSION: Investigators should think carefully before collecting baseline data in a cluster randomised trial if this is at the expense of endline data. In some scenarios, this will increase the sample size required to achieve given power and precision.

Sexual mixing in opposite-sex partnerships in Britain and its implications for STI risk: findings from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3).

BACKGROUND: The extent to which individuals are similar to their sexual partners influences STI-transmission probabilities, yet there is a dearth of empirical data, especially those representative of the population. METHODS: Analyses of data reported by 10 759 sexually active people aged 16-74 y interviewed for a British national probability survey undertaken in 2010-12. Computer-assisted self-interviews asked about partner numbers and characteristics of participants' three most recent partnerships (MRPs). Opposite-sex MRPs were weighted to represent all such partnerships in the past year (N = 16 451). Estimates of disassortative age mixing (≥±5-y difference), ethnic mixing (partner of a different ethnic group) and geographical mixing (partner from a different region/country when they first met) were calculated, stratified by gender, age group and partnership status (casual/steady). Multivariable regression examined how these disassortative mixing measures were associated with STI-risk measures: condom use at first sex together at the partnership-level and, at the participant-level, STI-risk perception and reporting STI diagnoses. RESULTS: Disassortative age mixing occurred in around one-third of opposite-sex partnerships, with men ≥5 y older in most cases, although this proportion varied by participant's gender and age group. Ethnic mixing occurred less frequently (11.3% of men's and 8.6% of women's partnerships) as did geographical mixing (14.1 and 16.3%, respectively). Disassortative mixing was more common among casual vs steady partnerships. Condom use at first sex was less likely in women's partnerships that were age-disassortative [adjusted odds ratio (AOR): 0.79, 95% confidence interval (CI): 0.69-0.95], whereas men reporting disassortative ethnic mixing were more likely to perceive themselves at STI risk (AOR: 1.76, 95% CI: 1.23-2.52) and report STI diagnoses (AOR: 2.37, 95% CI: 1.22-4.59). CONCLUSIONS: Disassortative mixing, although uncommon among opposite-sex partnerships in Britain, is independently associated with STI risk, warranting consideration in STI-prevention efforts.